Residency · Residency · Gastroenterology

Inflammatory Bowel Disease - Crohn Disease

Epidemiology and Pathogenesis

Epidemiology

Crohn disease has an incidence of 3 to 20 per 100,000 per year in North America and Europe, with a rising global incidence that is particularly notable in newly industrialized countries undergoing Westernization of diet and lifestyle. The age distribution is bimodal, with a primary peak between 15 and 30 years and a second, smaller peak between 50 and 70 years. There is a slight female predominance in adult populations. The prevalence is higher among Ashkenazi Jewish populations. Smoking is a critically important modifiable risk factor, increasing the risk of developing Crohn disease approximately 2-fold, which stands in direct contrast to ulcerative colitis, where smoking is paradoxically protective. Smoking worsens the disease course and increases the risk of surgical recurrence.

Pathogenesis

The pathogenesis of Crohn disease involves a dysregulated immune response to gut microbiota in genetically susceptible individuals exposed to environmental triggers. The NOD2/CARD15 gene on chromosome 16 was the first and remains the strongest Crohn disease-associated gene. It encodes a protein involved in bacterial peptidoglycan (muramyl dipeptide) recognition, and three major variants (R702W, G908R, and L1007fs) have been identified. Individuals who are homozygous or compound heterozygous for these variants carry a 20- to 40-fold increased risk and are associated with ileal disease location and a fibrostenotic phenotype. ATG16L1 and IRGM are autophagy genes whose variants impair bacterial clearance from the intestinal epithelium. The IL23R gene harbors a protective variant that reduces Th17-mediated inflammation. More than 200 IBD susceptibility loci have been identified, confirming the polygenic nature of disease risk.

At the microbiome level, patients with Crohn disease demonstrate decreased microbial diversity (dysbiosis) with specific alterations including reduced Firmicutes (especially the anti-inflammatory species Faecalibacterium prausnitzii) and increased adherent-invasive Escherichia coli (AIEC). Barrier dysfunction with increased intestinal permeability has been demonstrated to precede clinical disease onset in at-risk individuals.

Key Pathologic Features

The pathologic hallmarks of Crohn disease distinguish it fundamentally from ulcerative colitis. Transmural inflammation involving all layers of the bowel wall is the defining characteristic. Skip lesions, consisting of discontinuous segments of involved bowel separated by normal intervening areas, are characteristic of the disease. Non-caseating granulomas are present in 30 to 50% of surgical specimens and 15 to 30% of mucosal biopsies; while they are highly suggestive of Crohn disease, they are not pathognomonic. Creeping fat, in which mesenteric adipose tissue wraps around the bowel wall, correlates with transmural inflammation and fibrosis. The transmural nature of inflammation gives rise to the complications that define Crohn disease: fistulae, strictures, and abscesses.

Montreal Classification

The Montreal Classification provides a standardized framework for characterizing Crohn disease across three dimensions.

Age at diagnosis (A)

The classification recognizes three age groups: A1 for patients diagnosed before 16 years of age (pediatric onset, which often follows a more aggressive course), A2 for diagnosis between 17 and 40 years, and A3 for diagnosis after 40 years.

Location (L)

Disease location is classified as L1 for ileal disease (30 to 40% of patients), L2 for colonic disease (20 to 30%), L3 for ileocolonic involvement (40 to 50%, the most common location), and L4 as a modifier that can be added to any of the preceding categories to denote isolated upper gastrointestinal involvement.

Behavior (B)

Disease behavior is classified as B1 for non-stricturing, non-penetrating (inflammatory) disease, which accounts for approximately 70% of patients at the time of diagnosis but progresses in the majority within 10 years. B2 designates stricturing or fibrostenotic disease, and B3 designates penetrating or fistulizing disease. A perianal disease modifier (p) can be added to any behavior classification.

Clinical Presentation

Intestinal Manifestations

The intestinal symptoms of Crohn disease include chronic diarrhea lasting more than 4 weeks, abdominal pain (often localized to the right lower quadrant in ileal disease), and weight loss. Rectal bleeding is generally less prominent than in ulcerative colitis unless there is significant colonic involvement. Perianal disease, including fissures, fistulae, and abscesses, is present in 30 to 50% of patients overall and in 80 to 100% of those with rectal involvement, and may be the presenting manifestation. Oral aphthous ulcers are common. Patients with stricturing disease may present with nausea, vomiting, and obstructive symptoms.

Extraintestinal Manifestations

Extraintestinal manifestations are divided into those that correlate with intestinal disease activity and those that follow an independent course. Manifestations that parallel disease activity include peripheral arthritis (type 1 pauciarticular pattern), erythema nodosum, episcleritis, and oral aphthae. Manifestations that are independent of disease activity include axial spondyloarthropathy (sacroiliitis and ankylosing spondylitis, with HLA-B27 present in 50 to 70%), pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis (though PSC is more commonly associated with ulcerative colitis).

Metabolic complications of Crohn disease include metabolic bone disease, nephrolithiasis (calcium oxalate stones due to fat malabsorption increasing oxalate absorption), cholelithiasis (bile salt malabsorption from ileal disease), and thromboembolic disease (2- to 3-fold increased risk of venous thromboembolism, which may be the initial presentation of the disease).

<image>A comprehensive anatomical diagram showing the distribution and manifestations of Crohn disease throughout the GI tract and extraintestinal sites. Central image: full GI tract from mouth to anus with highlighted areas showing: oral aphthous ulcers (mouth), esophageal/gastric involvement (rare, upper GI), ileal disease (thickened terminal ileum with narrowed lumen and cobblestone mucosa), ileocolonic involvement (most common), skip lesions with normal intervening bowel, colonic disease, and perianal disease (fistulae, abscess). Surrounding the central image, show extraintestinal manifestations with arrows pointing to affected organs: eyes (episcleritis, uveitis), joints (sacroiliitis, peripheral arthritis), skin (erythema nodosum on shins shown as tender red nodules; pyoderma gangrenosum shown as undermined ulcer with violaceous border), liver (PSC with beaded bile ducts), kidneys (oxalate stones), and bones (osteoporosis). Include a cross-sectional inset of the bowel wall showing transmural inflammation with non-caseating granuloma, fissuring ulcer extending to serosa, and creeping fat. Label all structures clearly with leader lines.</image>

Diagnostic Workup

Laboratory

Laboratory evaluation reveals anemia, which may be due to iron deficiency, vitamin B12 deficiency, or anemia of chronic disease, along with leukocytosis and thrombocytosis reflecting active inflammation. C-reactive protein (CRP) correlates with disease activity and is useful for longitudinal monitoring. Erythrocyte sedimentation rate (ESR) is less specific but provides complementary information. Fecal calprotectin, a neutrophil-derived protein, is a highly useful biomarker: levels exceeding 250 mcg/g are highly suggestive of active mucosal inflammation. It serves triple duty in distinguishing IBD from irritable bowel syndrome at diagnosis, monitoring treatment response, and predicting relapse. Fecal lactoferrin has similar clinical utility. Serologic markers show that ASCA positivity (anti-Saccharomyces cerevisiae antibodies) favors Crohn disease while pANCA positivity favors ulcerative colitis, though neither marker is sufficiently sensitive or specific for diagnosis.

Endoscopy

Ileocolonoscopy with biopsies is the gold standard for diagnosing Crohn disease. Biopsies should be obtained from all segments, including the terminal ileum and each colonic segment, even when the mucosa appears macroscopically normal. Endoscopic findings range from the earliest manifestation of aphthous ulcers to linear and serpiginous ulcers, cobblestone mucosa (formed by ulcers surrounding islands of edematous mucosa), strictures, and fistula openings. The Simple Endoscopic Score for Crohn Disease (SES-CD) quantifies endoscopic severity and is used in clinical trials and the treat-to-target approach. The Crohn Disease Endoscopic Index of Severity (CDEIS) provides a more detailed but complex assessment.

Cross-Sectional Imaging

CT enterography (CTE) has a sensitivity of 85 to 95% for detecting active inflammation, evidenced by mural hyperenhancement, wall thickening exceeding 3 mm, fat stranding, and the comb sign (engorgement of mesenteric vasa recta). It also reliably detects complications including abscess, fistula, and obstruction. MR enterography (MRE) provides equivalent sensitivity without radiation exposure, making it preferred for younger patients and for serial monitoring. Diffusion-weighted imaging adds diagnostic value. Pelvic MRI is the gold standard for assessing perianal fistulae, providing detailed evaluation of the Parks classification and identifying abscesses. Small bowel video capsule endoscopy is reserved for suspected small bowel Crohn disease with negative cross-sectional imaging, with a patency capsule administered first to exclude strictures. The Lewis score quantifies capsule endoscopy findings.

Distinguishing CD from UC

The distinction between Crohn disease and ulcerative colitis rests on several key differences. Crohn disease can involve any segment from the mouth to the anus, whereas ulcerative colitis invariably involves the rectum and extends proximally in a contiguous fashion. Crohn disease produces transmural inflammation; ulcerative colitis affects only the mucosa and submucosa. Granulomas, skip lesions, fistulae, and perianal disease characterize Crohn disease, while crypt abscesses, pseudopolyps, and continuous inflammation characterize ulcerative colitis. In 5 to 10% of cases, the features overlap sufficiently to warrant a designation of IBD-unclassified.

Assessment of Disease Activity

Clinical Indices

The Crohn Disease Activity Index (CDAI) is a composite score in which values below 150 denote remission, 150 to 220 mild disease, 220 to 450 moderate disease, and above 450 severe disease. Its limitations include heavy weighting by subjective symptoms. The Harvey-Bradshaw Index (HBI) is a simplified version with corresponding thresholds: below 5 for remission, 5 to 7 for mild, 8 to 16 for moderate, and above 16 for severe disease. The Patient-Reported Outcome-2 (PRO-2), incorporating stool frequency and abdominal pain, has been validated for use in clinical trials.

Objective Markers

Non-invasive monitoring relies on CRP and fecal calprotectin. Endoscopic mucosal healing, defined as an SES-CD of 2 or less or the absence of ulceration, is the gold standard treatment target. Transmural healing on MRE or CTE, defined as normalization of wall thickness and enhancement, is an emerging target that may better predict long-term outcomes.

Treat-to-Target Strategy (STRIDE-II)

The STRIDE-II consensus defines a hierarchical set of treatment targets to guide therapeutic decision-making. Immediate targets focus on clinical response with improvement in symptoms. Intermediate targets include normalization of CRP and reduction of fecal calprotectin below 250 mcg/g. Long-term targets encompass endoscopic healing (absence of ulceration with SES-CD of 2 or less), resolution of complications, normalization of quality of life and disability scores, and transmural healing on cross-sectional imaging. Reassessment at regular intervals, typically every 3 to 6 months, with escalation of therapy when targets are not met, is fundamental to this approach.

Treatment Approach

Induction of Remission

Mild Disease

Mild Crohn disease involving the ileum or right colon is treated with budesonide 9 mg daily for 8 weeks, followed by a taper over 2 to 3 months. The role of 5-aminosalicylic acid (5-ASA) agents in Crohn disease is limited compared to ulcerative colitis. Sulfasalazine may have modest benefit in Crohn colitis, but mesalamine is not recommended for ileal Crohn disease.

Moderate-Severe Disease

Systemic corticosteroids, typically prednisone at 40 to 60 mg per day, are effective induction agents but have no role in maintenance therapy due to the risks of bone loss, adrenal suppression, and increased infection susceptibility. The goal is to achieve steroid-free status by 12 weeks. Biologic therapies are increasingly used as first-line agents for moderate-to-severe disease and are covered in detail in the IBD Therapeutics lecture. The available classes include anti-TNF agents (infliximab, adalimumab, and certolizumab), anti-integrin therapy (vedolizumab, which is gut-selective), anti-IL-12/23 therapy (ustekinumab), anti-IL-23 agents (risankizumab, guselkumab, and mirikizumab), JAK inhibitors (upadacitinib, approved for Crohn disease), and S1P receptor modulators (ozanimod, approved for ulcerative colitis and under study for Crohn disease).

Early Aggressive (Top-Down) Strategy

The early aggressive or top-down strategy advocates initiating biologic therapy with or without an immunomodulator upfront rather than following a traditional step-up approach. This strategy is supported by the REACT trial, which demonstrated that early combination of infliximab and azathioprine reduced complications, and the CALM trial, which showed that tight control with adalimumab escalation guided by biomarkers (CRP and fecal calprotectin) was superior to symptom-based management. The strongest evidence for early aggressive therapy applies to high-risk patients identified by young age at diagnosis, extensive disease, deep ulceration, perianal involvement, or prior surgery.

Maintenance of Remission

Maintenance therapy options include immunomodulators such as azathioprine at 2 to 2.5 mg/kg/day, 6-mercaptopurine at 1 to 1.5 mg/kg/day, or methotrexate at 25 mg subcutaneously weekly for induction followed by 15 mg weekly for maintenance. Biologic therapies are continued with ongoing scheduled maintenance dosing guided by therapeutic drug monitoring. The key treatment goal is steroid-free remission, and corticosteroids are never appropriate as maintenance agents.

Perianal Crohn Disease

The management of perianal Crohn disease requires a combined surgical and medical approach. Initial assessment involves examination under anesthesia combined with pelvic MRI for comprehensive evaluation. Simple perianal fistulae are treated with antibiotics (ciprofloxacin 500 mg twice daily plus metronidazole 500 mg three times daily for 6 to 12 weeks) and fistulotomy if superficial. Complex perianal fistulae require seton placement for drainage combined with anti-TNF therapy, with infliximab being preferred based on data from the ACCENT II trial. The DIAMOND trial supports the combination of anti-TNF with an immunomodulator. Perianal abscesses must be surgically drained before initiating medical therapy. Mesenchymal stem cell injection (darvadstrocel/Alofisel), approved in Europe, represents an emerging therapeutic option.

<image>A Parks classification diagram of perianal fistulae in Crohn disease. Show a coronal cross-section of the anal canal and surrounding structures with clearly labeled anatomy: internal anal sphincter, external anal sphincter, levator ani, puborectalis muscle, ischiorectal fossa, and intersphincteric space. Illustrate four fistula types with different colored tract lines: (1) Intersphincteric (red line) — track between internal and external sphincters opening at perianal skin; (2) Trans-sphincteric (blue line) — track through both internal and external sphincters into ischiorectal fossa; (3) Suprasphincteric (green line) — track over the top of the external sphincter through the levator ani; (4) Extrasphincteric (yellow line) — track from rectum above the sphincters through levator ani to perianal skin. Show a horseshoe extension in dotted lines. Include a small inset showing an axial pelvic MRI slice with a trans-sphincteric fistula tract highlighted (hyperintense on T2/STIR). Label the percentage frequency of each type.</image>

Surgical Management

Indications

Surgical intervention in Crohn disease is indicated for medically refractory disease, fibrostenotic strictures (as distinguished from inflammatory strictures), abscesses requiring drainage, complicated fistulae, dysplasia or malignancy, and growth retardation in pediatric patients. Approximately 50% of patients with Crohn disease require surgery within 10 years of diagnosis, and recurrence at the anastomosis occurs in 50 to 70% within 10 years of surgery.

Principles

Surgical principles in Crohn disease emphasize conservative resection with preservation of as much bowel length as possible, as there is no benefit to wide surgical margins. Strictureplasty is appropriate for short, fibrostenotic strictures, particularly when multiple jejunoileal strictures are present, as it preserves bowel length. Ileocecal resection is the most commonly performed operation for ileal Crohn disease. A laparoscopic approach is preferred when technically feasible.

Post-Operative Recurrence Prevention

Post-operative monitoring includes ileocolonoscopy at 6 to 12 months after surgery, with the Rutgeerts score used to grade neo-terminal ileal disease on a scale from i0 to i4. Scores of i2 through i4 indicate significant recurrence requiring treatment escalation. Risk stratification guides the selection of post-operative prophylaxis. Low-risk patients (first surgery, non-smoker, non-penetrating disease) may be managed with observation alone or thiopurine therapy. High-risk patients (smokers, penetrating disease, prior resection, or extensive disease) should receive anti-TNF therapy, preferably infliximab or adalimumab, initiated within 4 weeks of surgery, as supported by the PREVENT and POCER trials. Smoking cessation is the single most important modifiable risk factor for reducing post-operative recurrence.

Complications

Strictures

Strictures may be inflammatory, fibrostenotic, or mixed, and cross-sectional imaging with MRE or CTE helps differentiate these by assessing for mural enhancement (indicating active inflammation) or its absence (indicating fibrosis). Endoscopic balloon dilation is effective for short strictures less than 5 cm in length that are endoscopically accessible, with success rates of 70 to 90%, a perforation risk of 1 to 3%, and a recurrence rate requiring redilation of approximately 50%. Longer, complex, or recurrent strictures require surgical resection or strictureplasty.

Intra-abdominal Abscess

CT-guided percutaneous drainage is the preferred initial approach for intra-abdominal abscesses, with success rates of 70 to 90%. Antibiotics covering enteric organisms, such as ciprofloxacin plus metronidazole or piperacillin-tazobactam, are administered concurrently. Initiation of biologic therapy must be avoided in the presence of an undrained abscess due to the risk of sepsis. Delayed surgery is performed after successful drainage and medical optimization of the patient.

Malignancy Surveillance

Patients with Crohn disease carry a 20- to 30-fold increased risk of small bowel adenocarcinoma compared to the general population, though no established screening protocol exists. Colorectal cancer risk is elevated in patients with Crohn colitis to a degree similar to ulcerative colitis. Surveillance colonoscopy should begin 8 years after disease onset in patients with more than one-third of the colon involved.

Key Clinical Pearls

• Smoking cessation is the single most impactful lifestyle modification in Crohn disease — increases disease activity, surgical risk, and post-operative recurrence
• NOD2/CARD15 mutations are associated with ileal disease and fibrostenotic behavior
• Fecal calprotectin <250 mcg/g and normal CRP correlate with endoscopic remission — use for non-invasive monitoring
• STRIDE-II targets: treat to endoscopic healing (absence of ulceration), not just symptom control
• Early biologic therapy (top-down) is preferred for moderate-severe, high-risk patients (REACT, CALM trials)
• Post-operative prophylaxis with anti-TNF therapy in high-risk patients (PREVENT, POCER) significantly reduces endoscopic recurrence
• Always drain abscesses before starting biologic therapy
• Perianal fistulizing CD: combined surgical (seton) and medical (anti-TNF) approach is standard of care

References

1. Lichtenstein GR, et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol. 2018;113(4):481-517.
2. Torres J, et al. ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis. 2020;14(1):4-22.
3. Turner D, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative. Gastroenterology. 2021;160(5):1570-1583.
4. De Cruz P, et al. Crohn's disease management after intestinal resection: a randomised trial (POCER). Lancet. 2015;385(9976):1406-1417.
5. Colombel JF, et al. Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390(10114):2779-2789.

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